Project Summary. Depression has been described as a problem of impaired neuroplasticity (e.g., prefrontal synaptic depression) at the molecular level, and decreased cognitive flexibility and prefrontal cortex (PFC) control at the neurocognitive level. Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing molecular neuroplasticity; but surprisingly little is known regarding its effects on depressed patients' neurocognitive processing. We posit that ketamine will rapidly increase cognitive flexibility and the PFC's influence on affective regions, allowing for rigid, negative biases in cognition to be rapidly reversed. We further expect these neurocognitive changes will provide a clinical window of opportunity in which to introduce automated cognitive training techniques, which will consolidate adaptive forms of cognitive processing (specifically, positive implicit representations of self) while neuroplasticity remains high. Instantiating adaptive forms of processing after first `priming' the brain with ketamine represents a potentially synergistic treatment approach that could extend the acute effects of a single ketamine infusion beyond its typical 3-7 day window, efficiently fostering antidepressant effects that are both rapid and enduring. In this study, 150 patients exhibiting a target profile (self-reported impairments in cognitive flexibility; negative self- representations; and clinically elevated depression symptoms) will be randomized to receive a single infusion of ketamine or a psychoactive control (midazolam) and will complete measures designed to capture a proposed neurocognitive `signature of rapid relief.' This approach will extend molecular models of ketamine's antidepressant mechanisms to novel cognitive domains, revealing the neurocognitive state that tracks with rapid relief. We hypothesize to see increases in cognitive flexibility and directed connectivity from PFC to salience network regions, and corresponding decreases in one of the rigid, negative biases posited to be a key cognitive promoter of depression: negative representations of self (?depressive self-schemas?)?a cognitive pattern that has shown preliminary sensitivity to ketamine's rapid influence in our previous studies. In a fully factorial (2x2) design, patients will then be randomized to receive a brief computer-based cognitive training protocol during the post-infusion ?window of opportunity,? designed to implicitly reverse negative self- representations, instilling positive self-representations in their place, or a sham variant of the same training. Patients will be followed over 1 month acutely (with 6-month naturalistic follow-up) to assess whether active cognitive training enhances and/or extends the durability of ketamine's effects on depression and on the neurocognitive `signature of rapid relief.' After priming brain plasticity with ketamine, we expect that training positive self-representations will provide an exceedingly efficient, low-cost, portable, non-invasive, safe, and highly dissemination-ready strategy for extending ketamine's rapid antidepressant effects. This study will provide novel, integrative information on neurocognitive intermediaries bridging ketamine's molecular and mood effects, and will represent the first attempt to synergistically combine ketamine with a cognitive training intervention in order to exploit and extend ketamine's rapid effects.